Human brains are one fiftieth of our body's weight, and yet consume up to one fifth of the body's energy. Two thirds of the brain's energy consumption goes into making nerve cells fire, and one third into cell maintenance. Most of the brain's energy is chemical energy manufactured in the mitochondria and stored in the form of ATP. Mitochondria live as organelles within cells, including brain cells. The number of mitochondria per cell can range from one to thousands, depending on the energy needs of the cell. Energy-hungry brain cells contain thousands of mitochondria. Once inside the body cyanocobalamin is converted to adenosylcobalamin and methylcobalamin. Adenosylcobalamin is critical to the health and functioning of the brain's mitochondria while methylcobalamin is critical to the health and functioning of the rest of the brain's and body's cells.
Muscle cells have a large energy demand and require lots of ATP. Muscle cells also have a correspondingly high number of mitochondria, and are often the site of the body's soreness and pain. The current invention focuses on musculoskeletal pain.
The current invention discloses novel approaches to prevent and treat the malfunctioning or underperformance of the body's mitochondria and cells with methylcobalamin, and adenosylcobalamin, and their chemical precursor, cyanocobalamin, especially in the central and peripheral nervous systems. The inventor of the current invention puts forth the theory that by providing cyanocobalamin, methylcobalamin, and/or adenosylcobalamin in therapeutic doses to headache and body pain sufferers that their mitochondria will attain sufficient therapeutic concentrations of these essential micronutrients to survive, increase in number and function properly, thereby not creating the symptoms of certain types of headache and body pain.
The current invention differs substantially from prior uses of cobalamins, such as hydroxycobalamin to take up excess nitric oxide, or cobalamins to prevent IgE-mediated allergic diseases, neurogenic inflammation or cobalamins to repair nerve cell-insulating myelin sheath.
Cyanocobalamin, methylcobalamin, adenosylcobalamin and hydroxocobalamin each contain a biologically rare cobalt metal atom as a central feature. Around that cobalt is the active part of each molecule (i.e. the moiety) which is the location responsible for the unique type of chemical reactions that molecule causes to make happen. Attached to their central cobalt atoms; cyanocobalamin has a cyano group, methylcobalamin has a methyl group, adenosylcobalamin has an adeno group, and hydroxocobalamin has a hydroxyl (OH) group. Because of these distinct electromagnetic properties, each of these compounds plays a distinct biochemical role.
Cyanocobalamin, methylcobalamin, and adenosylcobalamin (the three chemicals pertaining to the current patent) differ in some important ways from hydroxocobalamin (which does not pertain to the current patent).
Once inside the body cyanocobalamin is converted to methylcobalamin and adenosylcobalamin, but not to hydroxocobalamin.
Hydroxocobalamin is known to scavenge nitric oxide (NO) which is associated with migraine. Hydroxocobalamin does this scavenging by trading its OH group connected to its central cobalt with the nitric oxide molecule. Because neither cyanocobalamin, nor methylcobalamin, nor adenosylcobalamin have the ability to scavenge nitric oxide, their ability to lessen the frequency and severity of headaches cannot be ascribed to nitric oxide scavenging.
In 1999 Merkus disclosed in U.S. Pat. No. 5,925,625 a method and composition for the prophylaxis and treatment of headaches using intranasal hydroxocobalamin. The current invention can be distinguished from Merkus' patent because the current invention discloses the use of different chemical entities, namely cyanocobalamin, methylcobalamin, and adenosylcobalamin. The current invention can be distinguished from Merkus' patent because Merkus describes a short-term treatment while the current patent describes a long-term treatment. The current invention can be further distinguished from U.S. Pat. No. 5,925,625 because Merkus states that “Oral, sublingual as well as nasal administration of vitamin B12 appeared to be ineffective treatments . . . ” while the current patent teaches away from Merkus because the current patent discloses that buccal and sublingual administration do indeed yield effective treatments for headache.
In 2001 Ernest T. Armstrong (the inventor of the current invention) disclosed in U.S. Pat. No. 6,255,294 a method to treat allergy using cobalamins. However, in U.S. Pat. No. 6,255,294 there is no mention of headache or migraine. In U.S. Pat. No. 6,255,294 the invention relied on a method for treating Immunoglobulin E (IgE) mediated atopic disease including allergic rhinitis and asthma. Such atopic diseases are a completely different class of disease and human condition with different causations and modes of action than the headaches and body pains disclosed in the current invention. The claims of U.S. Pat. No. 6,255,294 were approved with cyanocobalamin, methylcobalamin, and hydroxocobalamin, but not with adenosylcobalamin.
In 2002 van der Kuy showed in an unblinded, open-label study on 19 migraine patients that intranasal hydroxocobalamin can have an effect on migraine. The authors of the van der Kuy study hypothesize that hydroxocobalamin might be effective in migraine because of its nitric oxide-scavenging activity. Flaws in the van der Kuy study include the lack of a placebo group as a comparator, and the lack of any follow up after the last day the subjects received their last dose of medication which could have demonstrated (or not demonstrated) a persistence of effect. The current invention can be distinguished from van der Kuy's research because van der Kuy used hydroxocobalamin while the current invention discloses the distinct chemical entities of cyanocobalamin, methylcobalamin, and adenosylcobalamin. The current invention can be distinguished from van der Kuy's research because van der Kuy's treatment has a short-term persistence of effect while the current invention has a long-term effect. The current invention can be distinguished from van der Kuy's research because for all subjects van der Kuy showed essentially no reduction in severity (mean of 2.2 at baseline versus 2.1 at the end of the study, on a 0-3 scale). The current invention can be further distinguished from van der Kuy's research because van der Kuy's mechanism of action describes hydroxocobalamin as a nitric oxide (NO) scavenger. Nitric oxide is created and excreted by the body within a matter of hours. The important distinguishing point is that the current invention's mechanism of action most certainly is different than that of van der Kuy's invention because the scavenging of nitric oxide lasts only hours while the current invention has a persistence of effect lasts weeks, and perhaps months or years. (Van der Kuy, H et al. Hydroxocobalamin, a nitric oxide scavenger, in the prophylaxis of migraine: an open, pilot study. Cephalalgia, 2002, 22, 513-519.)
Dalsgaard-Nielsen performed a double-blind, placebo-controlled study on 29 patients (active n=15 and placebo n=14). During two months every two weeks 2 mg of cyanocobalamin were administered intramuscularly. The patients reported a: “Good result” active n=4 versus placebo n=2, and “Considerable improvement” active n=2 versus placebo n=5. The authors concluded that no therapeutic effect attributable to cyanocobalamin was demonstrated. (Dalsgaard-Nielsen A T, Trautmann J. Profylaktisk behandling of migraene med vitamin B12. Almindelige Danske Laegeforening 1970; 132:339-41.)
The authors of the van der Kuy study also hypothesize that since cyanocobalamin has no nitric oxide-scavenging activity, in contrast to hydroxocobalamin, it is not surprising that in the Dalsgaard-Nielsen trials on cyanocobalamin no effect was seen in migraine patients. Van der Kuy was correct about the lack of cyanocobalamin's nitric oxide-scavenging activity, but they missed another flaw in the Dalsgaard-Nielsen trials: Dalsgaard-Nielsen administered cyanocobalamin only once every two weeks. Based on the current inventor's original clinical research, the current invention teaches away from Dalsgaard-Nielsen and discloses a particularly preferred embodiment of daily administration of cyanocobalamin, with repeated delivery ranging from about 15 days to about 60 days.
The non-obviousness of the instant claims can be established by considering that oral (buccal) dissolving strip, sublingual lozenges and other disclosed means of introducing the headache and body pain opposing medications orally provide significant improvements over the prior art in that the dissolving strip are more convenient for the headache patient than a series of injections, or a nasal spray. Compared to an injection, or nasal spray, a dissolving strip or a sublingual lozenge is much more convenient because it takes from between one minute and five minutes to inject oneself or to administer a nasal spray. These few minutes may not seem like much, but to the headache patient, time is of the essence.
Another advantage is that people in pain do not want something stuffed up their nose or an injection in the body.
Among the surprising advantages of the dissolving strip and sublingual lozenge over the injection and nasal spray is that the headache patient would not be further irritated by a painful injection process or by a nasal spray up a sensitive nostril. This is an important aspect of the oral strip which comes in an easy to use soft plastic container because headache patients are often hypersensitive to bright lights (photophobia), shrill sounds (phonophobia), smells (osmophobia), and metallic objects touching the body. Such extraneous irritations are the last thing a headache sufferer would want at the time he or she is experiencing an episode of headache, thus the strips and sublingual lozenge differ in a significant way.
The significance of the difference between the oral dissolving medication and other delivery means becomes apparent when one examines the large numbers of people and money involved. There are between 30 and 50 million headache sufferers in the United States, thus if only ten percent can be provided an improvement, then some 3 to 5 million people will be helped. According the American Academy of Pain Medicine, pain affects more Americans than does diabetes, heart disease, and cancer combined. Back pain problems in the United States are reported to cost more than $100,000,000,000 annually.
Many large pharmaceutical companies have spent millions of dollars over many years investigating new medications for headache sufferers, but none of them have developed any medication with the safety profile, efficacy and ease of use afforded by the current invention.